Compositions

ABSTRACT

Agricultural compositions comprising paraesthetic agrochemicals, such as pyrethroids, and an amount of urea effective to reduce the paraesthetic effect of such agrochemicals.

This application is directed to an agricultural composition having animproved sensory effect. More particularly, this application is directedto an agricultural composition demonstrating a reduced level ofparaesthesia.

Certain agricultural compounds can, under various conditions, beparaesthetic to particularly sensitive subjects. This effect ismanifested normally by a burning or prickling sensation on the skin. Ithas now been found that the level of paraestheticity of agrochemicals inparticular pesticides including insecticides and acaricides can beappreciably reduced by employing such agrochemicals in conjunction withand amount of urea capable of reducing the paraesthetic effect of theemployed agrochemical.

This application particularly concerns insecticidal or acaricidalpesticides loosely referred to as "pyrethroids" in the art which can beparaesthetic. Representative pyrethroids, all of which are known, areallethrin, prallethrin, furethrin, acrinathrin, bifenthrin, cyfluthrin,cyhalothrin, cypermethrin, deltamethrin, cyphenothrin, permethrin,phenothrin, resmethrin, tefluthrin, tetramethrin, dimethrin,fenfluthrin, pyresmethrin, terallethrin, tralomethrin, tralocytrin,flumethrin, cycloprothrin, fenvalerate, fluvalinate, pyriproxyfen,etofenprox, fenpropathrin, lambda-cyhalothrin, esfenvalerate,alpha-cypermethrin, beta-cyfluthrin.

Pyrethroids are very active broad spectrum insecticides. Pyrethroids(including pyrethrins) can be grouped together based on their similaroverall shape, physical properties (especially polarity) and mode ofaction at nerve membranes. The changes in nerve membrane ionicpermeability are mediated by discrete molecular structures, called ionicchannels, which are formed by proteins embedded in the lipid matrix ofthe membrane. The control of sodium ion permeability through the nervemembrane is vital to nerve function and the resting membrane iselectrically polarized. Pyrethroids act stereoselectively on a smallfraction of the fast voltage-dependent sodium ion channels in excitablenerve membranes in several parts of the insect nervous system. The majorinitial effect is to delay the closing of the sodium ion channelactivation gate. The prolongation of the transient inward sodium ionmovement through the nerve membrane produces membrane depolarizationwhich causes eventually a block of nerve impulses and results in theintoxication symptoms typical for pyrethroids.

Particular pyrethroids of interest in this application are of theformula (I)

    X--C(O)--O--CHR.sub.1 --Y                                  (I)

wherein

X is ##STR1## Y is 3-phenoxyphenyl wherein the phenyl is optionallyhalogen substituted; or 5-benzyl-3-furyl;

R₁ is hydrogen or cyano;

R₂ and R3 are independently selected from halogen; C₁₋₄ alkyl optionallysubstituted by halogen; phenyl optionally substituted by halogen; andC₂₋₅ alkoxycarbonyl;

R4 and R₅ are independently selected from hydrogen; halogen; and C₁₋₄alkyl optionally substituted by halogen;

R₆ is C₁₋₄ alkyl; and

n is 0 or 1.

Alkyl as used herein includes both branched and unbranched carbonchains.

Halogen as used herein includes chloro, bromo and fluoro.

R₁ is preferably cyano.

R₂ and R₃ are preferably selected from halogen, methyl, trifluoromethyland phenyl substituted by chloro.

R₄ and R₅ are preferably selected from hydrogen, chloro andtrifluoromethyl.

R₆ is preferably isopropyl.

Particular compounds or interest of the formula (I) are fluvalinate,fenvalerate and cypermethrin.

Compounds of the formula (I) and procedures for their syntheses areeither known or in cases of novel compounds, can be produced accordingto procedures which are analogous to know procedures.

Compositions containing the active ingredient and urea can be formulatedin the same manner as is known for formulating the active ingredient perse. They may be employed in either solid or liquid forms, e.g. in theform of a wettable powder or an emulsifiable concentrate incorporatingconventional diluents. Such compositions may be produced in aconventional manner, e.g. by mixing the active ingredient with a diluentand optionally other formulating ingredients such as surfactants.

The term diluents as used herein means any liquid or solidagriculturally acceptable material which may be added to the activeconstituent to bring it in an easier or improved applicable form,respectively to a usable or desirable strength of activity. It can forexample be talc, kaolin, diatomaceous earth, xylene or water.

Particular formulations to be applied in spraying forms such as waterdispersible concentrates or wettable powders may contain surfactantssuch as wetting and dispersing agents, e.g. the condensation product offormaldehyde with napththalene sulphonates, an alkylarylsulphonate, alignin sulphonate, a fatty alkyl sulphate, an ethoxylated alkylphenoland an ethoxylated fatty alcohol.

In general the formulations include from 0.01 to 90% by weight of thecombination of active agent and urea, from 0 to 20% by weight ofagriculturally acceptable surfactant and 99.99 to 10% by weight (solidor liquid) diluent(s).

The proportion of urea to active ingredient will vary according to use,particular type of active ingredient, etc. but will typically range inparts by weight urea:active ingredient from 0.001:1 to 4:1, e.g. from0.001:1 to 2:1. Particularly good results are obtained when the weightby weight proportion of urea to active ingredient is in the range offrom 1:25 to 4:1, more particularly in the range of from 2:1 to 4:1.

The compositions of this application can be employed to combat insectsand/or acari using application techniques and dosage rates that areknown for the active ingredient.

EXAMPLE Assessment of influence of urea on pyrethroid mediated skinsensory stimulation effects on guinea pig flank model

Test product MAVRIK Aquaflow containing 22.6% by weight oftaufluvalinate is applied at concentrations of 10%, 5%, 2.5% and 1% byweight a.i., respectively, by dilution in water, without or with theaddition of 10%, 5%, 2.5% and 1% by weight of urea, in a volume of 0.1ml.

Dosage per animal

0.1 ml of the test product is spread over a clipped area of approx. 30mm×30 mm of the right flank of the animal. 0.1 ml of water serves as thevehicle control applied to a clipped area of 30 mm×30 mm at the leftflank. Clipping of the fur is done approx. 24 hrs. before theapplication of the test product. The skin is inspected immediatelybefore application for signs and reactions to clipping.

Pilot study

The maximal dose-response for each concentration and the time course forreaching the peak in the evoqued sensory effect is determined in a pilotstudy using two animals per selected dose level (10%, 5%, 2.5% and 1%)of MAVRIK Aquaflow. The effect of urea versus water is evaluated usingtwo animals.

After a waiting period of at least one week after the dose application,each experiment is repeated in the same animal using now the test siteas the control site and vice versa. So, each concentration of MAVRIKAquaflow is tested twice per animal.

Main Study

The concentration of MAVRIK Aquaflow which gives the optimaldose-response in the pilot study is used in the main study. Fourconcentrations of urea are evaluated: 10%, 5%, 2.5% and 1%. Four animalsare assigned for each dose evaluation of urea. The experiment is alsoduplicated per animal using the test site as the control site and viceversa.

Behavioural responses

Behavioural observations are made starting at 3 hrs till 15 hrs (inmaximum) after each dose application. In the dark period a dim light(<100 Lux) is used. This observation period is shortened in the mainstudy to cover a reasonable time period after the peaking in activityhas been determined in the pilot study.

For each animal and each dose group the behavioural reactions arecontinuously recorded with an unmanned video camera using up to four(long play) or eight (normal play) videotapes.

Thus, each video tape covers an observation period up to 90 min. or 3hrs in maximum. The monitor is placed outside the animal room. Reactionssuch as licking or biting the test sites are quantified by counting thenumber of times the animals responds (head-turns) to the pyrethroid/ureapainted test site versus the untreated control site. Only fullhead-turns are taken into account. Mean values and S.D. are calculatedfrom the number of reactions revealed by each concentration tested.

For reporting, a 5-min. period is considered as the standard time unitfor the assessment of the behavioural reactions. One such time unit perhour of recording is regarded as sufficient to evaluate thedose-dependent behavioural reactions.

Statistical Analysis

To determine if the test product causes greater stimulation than thevehicle alone, and if the test compound alone produces a greaterstimulation than the test compound to which urea was added, the responsefor each animal to the test flank is compared to the response to thecontrol flank and by taking into account any modulatory effect of urea,respectively.

Based on the observations it can be concluded that urea has aninhibitory effect on the pyrethroid-induced skin sensory stimulationeffect in the guinea pig flank mode.

For test concentrations of 2.5% active ingredient of MAVRIK® Aquaflowthe inhibitory effect is particularly pronounced after addition of 5%and 10% of urea.

I claim:
 1. A method of reducing the paraesthetic effect of a pyrethroiddemonstrating paraesthesia on a host susceptible to paraesthesia whichcomprises employing said pyrethroid in conjunction with an amount ofurea capable of reducing the paraesthetic effect of said pyrethroid. 2.The method of claim 1, wherein the pyrethroid is of formula (I)

    X--C(O)--O--CHR.sub.1 --Y                                  (I)

wherein X is ##STR2## Y is 3-phenoxyphenyl wherein the phenyl isoptionally halogen substituted; or 5-benzyl-3-furyl; R₁ is hydrogen orcyano; R₂ and R₃ are independently selected from halogen; C₁₋₄ alkyloptionally substituted by halogen; phenyl optionally substituted byhalogen; and C₂₋₅ alkoxycarbonyl; R₄ and R₅ are independently selectedfrom hydrogen; halogen; and C₁₋₄ alkyl optionally substituted byhalogen; R₆ is C₁₋₄ alkyl; and n is 0 or
 1. 3. The method of claim 2,wherein the pyrethroid is cypermethrin, fenvalerate or fluvalinate.